Second-generation Basal Insulin Analogues in Type 2 Diabetes Mellitus Management
Second-generation Insulin Analogues – a Review of Recent Real-world Data and Forthcoming Headto-head Comparisons Second-generation Basal Insulin Analogues in the Management of Type 2 Diabetes Didac Mauricio
Comparative Efficacy and Safety of Second-generation Basal Insulin Analogues – a Review of Emerging Comparative Data Irene Hramiak
European Endocrinology SUPPLEMENT
www.touchENDOCRINOLOGY.com E UROPEA N EN DOCRIN O L OG Y
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Second-generation Insulin Analogues
Second-generation Insulin Analogues – a Review of Recent Real-world Data and Forthcoming Head-to-head Comparisons Didac Mauricio1 and Irene Hramiak2 1. Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; 2. Lawson Research Institute, London, ON, Canada DOI: https://doi.org/10.17925/EE.2018.14supp1.2
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nsulin analogues play a key role in the effective management of type 2 diabetes. However, there are several behavioural barriers to appropriate early initiation of insulin therapy, despite compelling evidence supporting the benefits of this strategy in those patients for whom oral anti-diabetes agents provide insufficient control. The development of second-generation insulin analogues (insulin glargine 300 U/mL and insulin degludec) has provided physicians with agents that can provide comparable glycaemic control to first-generation insulin, but with a reduced risk of hypoglycaemia and modes of action suited to once-daily regimens. These characteristics may help overcome patient and physician concerns about early insulin use in disease management. To date, there have been no head-to-head comparisons of second-generation insulins: here we consider recent real-world evidence and the forthcoming direct comparison in the BRIGHT randomised controlled study, as presented at the recent 11th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2018.
Keywords Second-generation, insulin glargine 300, once-daily insulin, hypoglycaemia, type 2 diabetes Disclosures: Didac Mauricio reports personal fees from Sanofi, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, GlaxoSmithKline, Novo Nordisk, Ferrer, Menarini, AstraZeneca and Janssen, outside the submitted work. Irene Hramiak reports grants from Lexicon Pharmaceuticals and Medtronic; grants and personal fees from Sanofi, GlaxoSmithKline, Janssen Pharmaceuticals and Novo Nordisk; personal fees from Amgen Inc, Boehringer Ingelheim, Roche, Insulet Corp and Takeda; grants, personal fees and non-financial support from Astra Zeneca/Bristol-Myers Squibb; and grants, personal fees and other support from Eli Lilly and Merck, outside the submitted work. Review Process: This supplement did not undergo the journal’s standard peer review process but was reviewed by the Editorial Board for scientific accuracy before publication. Acknowledgements: Editorial assistance was provided by Touch Medical Media and was funded by Sanofi. Received: 30 April 2018 Published Online: 11 May 2018 Citation: European Endocrinology. 2018;14(Suppl 1):2–9 Open Access Statement: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. © The Authors 2018. Corresponding author: Irene Hramiak, PO Box 5777, Station B, 268 Grosvenor St, London, Ontario, Canada, N6A 4V2. E:
[email protected] Support: The publication of this supplement is supported by Sanofi. The views and opinions are those of the authors and not necessarily those of Sanofi.
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Print Publication Date: 11 May 2018
Second-generation Basal Insulin Analogues in the Management of Type 2 Diabetes Didac Mauricio Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
The role of insulin in type 2 diabetes management and challenges to optimal initiation Type 2 diabetes mellitus (T2DM) is a progressive disease, and many patients eventually require intensification of therapy from oral anti-diabetes agents. Basal insulin therapy is a cornerstone of T2DM management for patients who do not achieve glycaemic control following intensification of oral-therapy regimens.1,2 Insulin is an effective option for those with long-standing diabetes, and may be considered as a direct addition to metformin in patients with uncontrolled hyperglycaemia.1–6 However, there are psychological and behavioural considerations associated with insulin treatment – from both the perspective of the patient and of the physician – that may result in basal insulin therapy being frequently and inappropriately delayed.7 Patients often see insulin therapy as inconvenient, potentially painful, as a treatment of ‘last resort’ and an indication of failure to manage their disease.2,8 Physicians may be reticent to initiate the ‘final’ option of the recommended stepwise treatment algorithms, and typically share concerns with their patients over weight gain, burden of injections, and an increased risk of hypoglycaemia.1,2,8,9 Indeed, a recent large-scale (n=40,627) real-world study found that the majority of patients did not achieve a target glycated haemoglobin (HbA1c) of ≤7% in the first 3 months or after 2 years, following initiation of basal insulin treatment; the authors noted the role that treatment inertia might play in avoidable, inadequate glycaemic control.10 After initiation of basal insulin, delays in escalating titration (i.e. clinical inertia) have also been observed, contributing to suboptimal glycaemic control.11,12
Overcoming treatment inertia and appropriate insulin initiation Patient concerns should be managed through education,8,13 which might include the benefits of glycaemic control, both in the short term and in terms of reduced complications in the longer term, and how appropriate insulin initiation using a personalised treatment approach can help achieve this.
TOUC H ME D ICA L ME D IA
Second-generation Basal Insulin Analogues in Type 2 Diabetes Mellitus Management
Physicians should consider that stepwise management algorithms typically wait for a treatment to be ineffective before escalation to, or addition of, another agent. This ‘wait for failure’ approach often means that patients may not be initiated on insulin therapy for relatively long periods of time,2,14,15 although current treatment recommendations from the American Diabetes Association and the European Association for the Study of Diabetes highlight that target achievement should be evaluated 3 months after a change of treatment has been made.1,2 Suboptimal glycaemic control arising from treatment inertia has been observed in patients receiving oral anti-diabetes drugs (OADs), with notable delays in treatment escalation and a median of over 7 years before initiation of insulin treatment.15 In patients receiving three OADs, the probability of adding an OAD or initiation of insulin was 5.7% after 1 year (no patients received a fourth OAD), and mean HbA1c was 9.7% at the point of intensification to insulin.15
Table 1: Long-term* benefits of reducing hyperglycaemia in patients with type 2 diabetes mellitus
However, there exists compelling evidence to support a more active and target-driven approach, with long-term studies demonstrating the benefits of early target-driven treatment of hyperglycaemia in terms of reducing micro- and macro-vascular complications (Table 1).16,17 Reductions in risk of microvascular disease, myocardial infarction and death achieved with a median of 10 years of intensive glycaemic control16 were maintained during 10 years of post-trial follow-up.17 Treat-to-target management can be supported with a personalised treatment approach, using timely escalation through step-wise guidelines to achieve tight glycaemic control and reduce unnecessary glycaemic burden resulting from delayed or suboptimal intervention.2,14,15
*Median 10 years. HbA1c = glycated haemoglobin. Information source: Stratton et al., 2000.16
Outcome
Risk reduction for each 1% decrease in HbA1c over a median 10-year period
Death related to diabetes
21%
All-cause mortality
14%
Fatal and non-fatal myocardial infarction
14%
Fatal and non-fatal stroke
12%
Microvascular endpoints
37%
Cataract extractions
19%
Amputation or death from peripheral vascular
43%
disease Heart failure
In recent years, significant advances have been made in basal insulin therapy. The second generation of basal insulin analogues offers compelling therapeutic benefits over first-generation insulin therapies, which may help physicians and patients overcome some of the barriers to initiation and intensification of insulin treatment.18–23
Figure 1: Mean glucose infusion rate profiles of insulin glargine 300 U/mL and insulin degludec at the 0.4 U/kg/day dose level in steady state Mean glucose infusion rate (mg/min/kg)
Era of the second-generation basal insulin analogue
16%
3.5 3.0
Gla-300 (0.4 U/kg) IDeg (0.4 U/kg)
2.5 2.0 1.5 1.0 0.5 0.0
0
2
4
6
8
10
12
14
16
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20
22
24
26
28
30
Time after closing on day 8 (hours) Treatment ratio (Gla-300/IDeg): 0.80 (90% CI: 0.66 to 0.96), p=0.047
Second-generation basal insulin analogues (insulin glargine 300 U/ mL [Gla-300; Sanofi, Paris, France] and insulin degludec [IDeg; Novo Nordisk, Bagsværd, Denmark]) have demonstrated similar efficacy in reducing HbA1c to first-generation insulin therapy (e.g. insulin glargine 100 U/mL [Gla-100; Sanofi]).18 However, the newer agents have longer and more stable pharmacokinetic (PK) and pharmacodynamic (PD) profiles than first-generation treatments.19–23 Gla-300 is associated with low within-day variability and high reproducibility (low betweenday variability) in insulin exposure,19,24 with predictable and stable glycaemic control well beyond 24 hours.25 Similarly, IDeg has demonstrated activity for up to 42 hours with four times lower dayto-day within-patient variability in glucose reduction compared with Gla-100.20 A comparison of the steady state PK/PD profiles of Gla300 and IDeg revealed that Gla-300 provided 20% less within-day fluctuation of metabolic activity than IDeg over 24 hours at a dose of 0.4 U/kg/day (Figure 1).26 These advances have translated into the clinically meaningful benefit of providing similar glycaemic control to Gla-100, but with an ultra-long duration (>24-hour coverage), a more stable PK profile (resulting in reduced glycaemic variability), and greater injection time flexibility. These
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CI = confidence interval; Gla-300 = insulin glargine 300 U/mL; IDeg = insulin degludec. Reproduced under the CC-BY-NC license from Bailey et al., 2018.26
factors make second-generation basal insulin analogues suitable for once-daily treatment.19–23 In addition to effectively reducing HbA1c, the second-generation basal insulin analogues are associated with a lower risk of hypoglycaemia (both nocturnal hypoglycaemia and also, for Gla-300, all-day hypoglycaemia) compared with Gla-100 (Figure 2).18,27,28 For Gla-300, the benefit of lower incidence of hypoglycaemia is especially pronounced in the titration period.29
Concluding remarks The second-generation basal insulin analogues provide physicians with new treatment options for achieving targeted glycaemic control. While providing similar efficacy in lowering HbA1c to first-generation insulin analogues, the newer insulin treatment options provide additional clinical benefits, including a more stable, ultra-long duration of action that enables once-daily administration with flexibility in daily injection time, together with a lower risk of hypoglycaemia. ❒
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Second-generation Insulin Analogues Figure 2: Meta-analysis assessment of the risk of nocturnal and anytime hypoglycaemia or severe hypoglycaemia with second-generation insulins compared with insulin glargine 100 U/mL
IDeg versus Gla-100 (BEGIN Trials)
Gla-300 versus Gla-100 (EDITION Trials)
Confirmed (
